Systemic lupus erythematosus (SLE) is an idiopathic autoimmune disorder of indeterminate etiology characterized by the T cell's inability to carry out programmed physiological immune effector functions, including help and cytotoxicity. Our laboratory identified the first disorder of T cell signaling involving the cAMP/protein kinase A (PKA) pathway. There is a profound deficiency of PKA phosphotransferase activity due to diminished type I (PKA-I) and type II (PKA-II) isozyme functions. Deficient PKA-II activity is associated with abnormal nuclear translocation of the beta isoform of the regulatory subunit from the cytosol and its retention in the nucleus. I hypothesize that nuclear RII beta-subunit in SLE T cells is a transcriptional repressor of the c-Fos gene. RII beta-subunit is predicted to bind to the nuclear transcription factor, cAMP response element binding protein (CREB), preventing CREB form binding to the cAMP response element (CRE) of the c-Fos gene and thereby inhibiting the gene's transcriptional activation. Transcriptional repression of c-Fos indirectly diminishes the generation of IL-2. This mechanism may contribute to impaired IL-2 production by SLE T cells.